Oxybutynin is an anticholinergic, antispasmodic agent that has been known since the mid 1960s and has been used for the treatment of overactive bladder and urinary incontinence. Oxybutynin has a chiral molecular center and may be present as a racemic mixture or in purified isomeric forms. Oxybutynin, as well as the purified isomeric forms, can be prepared as a free base or as a pharmaceutically acceptable salt form such as the chloride salt. Oxybutynin is metabolized to desethyloxybutynin which is believed to have pharmacological activity similar to oxybutynin.
Oxybutynin has been commercially available in the form of oral syrups, immediate release tablets, controlled release osmotic tablets and transdermal patches. Examples of oral controlled release oxybutynin formulations are disclosed in U.S. Pat. Nos. 5,674,895; 5,912,268; 6,262,115 and 6,919,092. The oral administration of oxybutynin is known to cause a number of adverse side effects. The primary adverse side effect is dry mouth, however, adverse events such as abdominal pain, dry nasal and sinus mucous membranes, constipation, diarrhea, nausea, somnolence, dizziness, impaired urination, increased post void residual volume and urinary retention have been reported.
It has been discovered that the incidences of adverse events can be reduced by the transdermal administration of oxybutynin. Transdermal oxybutynin patches are described, for example, in U.S. Pat. Nos. 5,164,190; 5,601,839; 6,743,441 and 7,081,249. Examples of non-occluded oxybutynin topical compositions are described, for example, in U.S. Pat. Nos. 7,029,694; 7,194,483 and 7,425,340. It has been reported that the transdermal administration of oxybutynin results in a reduced oxybutynin:desethyloxybutynin ratio in the plasma compared to the oral administration of oxybutynin. This reduced oxybutynin:desethyloxybutynin ratio via transdermal administration results in less adverse events.
Although oxybutynin transdermal patches and non-occluded topical compositions are known in the art and provide the benefits of oxybutynin without the increased side effects of oral administration, the development of a suitable device, container and/or packaging system for storing and administering non-occluded oxybutynin topical compositions has been problematic. Specifically, the storage and administration device needs to provide an accurate and consistent dose of oxybutynin to insure the patient receives the necessary therapeutic amounts of the drug. The device also needs to provide a stable and robust environment for the non-occluded oxybutynin topical composition. With respect to stability, the device must prevent the non-occluded oxybutynin topical composition from degrading over time, reacting with the materials forming the device and leaching or permeating through the device.
The stability of non-occluded oxybutynin topical compositions further presents many unique issues because the non-occluded oxybutynin topical compositions often contain a high solvent content, i.e., water or alcohol. The high solvent content may promote reactions with the materials forming the storage and administration device. The solvent may also evaporate, leach and/or permeate from the storage and administration device over time thereby resulting in a decreased skin flux when the non-occluded oxybutynin topical composition is dispensed and applied to a patient's skin.
Further stability complications can occur when oxybutynin chloride is employed. The large volume of solvent in the non-occluded oxybutynin topical composition will allow the oxybutynin chloride salt to disassociate, creating free chloride ions that may cause further unwanted reactions with materials forming the storage and administration device.
A device for storing and administering non-occluded oxybutynin topical compositions must also be strong, durable and useable. Specifically, the device must protect the non-occluded oxybutynin topical composition from accidentally or prematurely being dispensed or expelled from the device. For example, the device may be inadvertently squeezed, crushed or compressed during storage and transport to the patient. The device must withstand these inadvertent compressive forces without bursting but allow the patient to easily open and dispense the non-occluded oxybutynin composition.
Containers for cosmetic and pharmaceutical products such as alcohol pads, transdermal patches and perfumes are described in the art. For example, WO 90/05683 describes a heat sealed sachet that can be used to store cosmetic and pharmaceutical materials wherein the layers of the sachet can be peeled apart to allow access to the stored material without touching the stored material. This structure would not be useful for a non-occluded oxybutynin topical composition because the sealing bond strength is low and may causing unwanted bursting.
Another container is disclosed in WO 85/03275 which describes a container for an alcohol preparation device that employs a fluid retaining pad sandwiched between two fluid impermeable layers. Still other flexible containers are taught in GB 515,876 as well as in U.S. Pat. Nos. 4,998,621; 5,268,209; 5,400,808; 6,326,069; and 6,905,016. These prior container systems employ support structures for stored materials.
None of these prior containers suggest their use with a non-occluded oxybutynin topical composition, and, more importantly, a way to overcome the stability, strength and durability issues encountered when preparing a device for storing and administering a non-occluded oxybutynin topical composition.
It is an object of the present invention to provide a device for storing and administering a non-occluded oxybutynin topical composition that can provide an accurate and consistent dose of oxybutynin to a patient.
It is a further object of the present invention to provide a device for storing a non-occluded oxybutynin topical composition that provides a stable environment for the non-occluded oxybutynin topical composition for at least one year or longer.
It is another object of the present invention to provide a device for storing and administering a non-occluded oxybutynin topical composition that is strong, durable and robust to avoid unwanted and accidental ruptures or bursts under pressure of at least 20 pounds, preferably at least 25 pounds and most preferably at least 30 pounds of pressure or more.
It is still a further object of the present invention to provide a device for storing and administering a non-occluded oxybutynin topical composition that is easy to manufacture and is free of any rigid structural support mechanisms.
It is yet another object of the present invention to provide a device for storing and administering a non-occluded oxybutynin topical composition that is easy to open and from which the non-occluded oxybutynin topical composition is easily dispensed.
It is still another object of the present invention to treat human patients suffering from overactive bladder by providing to a patient a single or daily dose of a therapeutically effective amount of a non-occluded oxybutynin topical composition in a flexible storage device, removing or dispensing the single or daily dose of the non-occluded oxybutynin composition from the flexible storage device and topically applying the single or daily dose of the non-occluded oxybutynin composition to the patient's skin.
These and other objects of the present invention will become apparent from a review of the appended specification.